Rhabdomyosarcoma (RMS) is a rare pediatric soft tissue sarcoma grouped into alveolar (ARMS), embryonal (ERMS), and other histological subtypes. ARMS is associated with older patients and chromosomal translocations encoding a fusion gene involving FKHR on chromosome 13 and members of the PAX gene family. Embryonal RMS is characterized by a younger age at diagnosis, loss of heterozygosity and altered patterns of genomic imprinting. An important determinant of long term survival in all subtypes is the absence of metastatic disease, although a third of patients either present or relapse with metastases, succumbing to this fatal stage of malignancy. A major deficit in the present understanding of cancer pathophysiology is the identity of the genetic events controlling development of tumor metastases.
Fibroblast growth factor receptors (FGFRs) are of great interest in cancer biology as they regulate essential processes including cellular survival, motility, development, and angiogenesis. In humans, FGFRs have a highly conserved amino acid sequence across family members including FGFR1, FGFR2, FGFR3, and FGFR4. These cell surface receptors consist of extracellular immunoglobulin-like domains, a transmembrane domain, and an intracellular tyrosine kinase (TK) domain. FGFR4 has been shown to be overexpressed in a variety of cancers, including rhabdomyosarcoma, prostate cancer, breast cancer, and lung cancer (Khan et al., Nat. Med. 7:673-679, 2001; Sahadevan et al., J. Pathol. 213:82-90, 2007; Bange et al., Cancer Res. 62:840-847, 2002).
Metastasis, the spread of a tumor from its primary site to other parts of the body, continues to be the most significant problem in the field of cancer. Patients who present with metastatic disease or those who develop metastases after successful management of the primary tumor carry a universally poor prognosis.